Pump control apparatus for cellular filtration systems employing rotating microporous membranes

ABSTRACT

A system for separating at least one constituent from a liquid suspension such as blood induces high velocity flow by viscous drag about the circumference of a spinner having a filtration membrane with pore sized selected for the desired constituent. The high velocity circumferential flow is bounded by a spaced apart shear wall, with a spacing selected relative to the diameter of the spinner and its rotational velocity, also with respect to the viscosity of the suspension, to establish a flow within the shear gap, as substantial centrifugal forces are exerted upon the suspension. Under these conditions, filtrate in contact with the membrane is replenished and filtrate passes through the membrane with minimal adverse effects from deposition and concentration polarization, and with high efficiency because of high shear levels that are maintained. The filtrate is collected within the interior of the spinner in a conduit system and passed to an outlet orifice.

This is a continuation of copending application Ser. No. 07/732,420filed on Jul. 18, 1991, now abandoned, which is a division of Ser. No.07,052,171 filed May 8, 1987 (now U.S. Pat. No. 5,034,135) which is acontinuation of Ser. No. 07/449,470 filed Dec. 13, 1982, now abandoned.

BACKGROUND OF THE INVENTION

Blood is a living, complex, and in many respects unstable system, andany processes which seek to separate affect the characteristics of itsconstituents must be carried out with due concern for these properties.Many medical procedures are based upon the separation of whole bloodinto particular constituents, whether processing homogeneous masses suchas plasma or extracting formed or discrete elements such as red bloodcells, platelets and leukocytes. More recently there has been a greatincrease in therapeutic treatments (therapeutic apheresis) in whichdifferent components in the blood complex can be processed or removed toattenuate diseases or destroy harmful organisms. The separation of theconstituents of whole blood, without damage, is fundamental to theplasma collection industry, therapeutic apheresis, and numerousbiomedical procedures. Blood separation processes have been widelyinvestigated and discussed in the scientific and patent literature, notonly because of their importance but because they present particularlycritical and difficult examples of the general problem of separating andremoving suspended constituents from a solution.

Workers in the art have relied on one of two fundamentally differentapproaches, namely centrifugation and membrane separation, to separatethe constituents of blood. Centrifugation, or stratification under theinfluence of centrifugal forces, may be realized on a continuous as wellas a batch basis. Adequate centrifugation intervals provide a highdegree of stratification and high yields. For continuous centrifugationa probe or other separator mechanism in the path of a particular layer(e.g. plasma) removes the selected constituent. However, long residencetimes, typically several minutes to several hours, and sometimesobjectionable additives as well are required for sharply definedstratification. Even with long residence times some residualconcentration of cells may remain in the plasma or extracted cellularcomponent. In addition, rotating seals must be used that are exposed tothe liquid in such a way that they present difficulties withinsterility, leakage and contamination. The presence of a probe or otheroutlet in a continuous centrifuge system requires some membrane orfilter shielding to prevent drawing off undesired constituents with theselected stratified layer. Because such a membrane or filter becomesexposed to a highly concentrated cellular mass that tends to be drawntoward the orifice, and because of the active propensity of bloodconstituents for adhering to and coating foreign substances, plugging orblocking of the conduits ultimately occurs.

Centrifugation can be used to obtain in excess of 90% recovery of aselected constituent such as plasma, and is the most widely employedsystem despite the problems mentioned and the manual steps required.Some commercial hemapheresis systems are based upon membrane filtrationtechniques because disposable modules can be used to provide essentiallycell free fluid separations quite rapidly. Filtration rates andrecoveries have been improved by flowing whole blood tangential to amembrane, with viscous shear acting on the flow so as to prevent redcells (in the case of plasma extraction) from exuding into the membranepores to plug them. The application of the shear principle to separationof blood, previously known in other fields, was apparently firstproposed for the separation of plasma by Blatt et al in an articleentitled "Solute Polarization and Cake Formation in MembraneUltrafiltration: Cause, consequences and control techniques", inMembrane Science and Technology, Plenum Press, New York 1970, pp. 47-97,and by Blatt in U.S. Pat. No. 3,705,100. Intensive investigation of theliterature has led to widely recognized understandings that certainparameters are crucial. These are the shear rate, the hematocrit(percentage of cells), plasma flux per unit area, transmembranepressure, blood flow resistance, sieving coefficient (percent of speciestransmitted) and hemolysis (measured as percent hemaglobin in plasma).The limiting factors on performance are regarded in the literature asbeing deposition or "fouling" and polarization concentration. The formerfactor pertains to the plugging of membrane pores by the entrapment oradhesion of cellular or protein matter, or both, and the latter relatesto the limits imposed on transport of blood constituents when a highconcentration of suspended matter exists near the membrane. As plasma iswithdrawn from whole blood the hematocrit increases so that with 90%plasma recovery and a hematocrit of 50%, for example, the return to thedonor is about 91% cells, which comprises an extremely concentrated cellmass. Even with the best designed prior art systems, the flow of plasmathrough the membrane is more than approximately two orders of magnitudesmaller than would be the flow through a membrane exposed only to pureplasma. The formed elements in suspension in the blood clearly are thecause of such limitations. In consequence, large membrane areas arerequired to recover relatively modest amounts of plasma (e.g. 50% ofinflowing plasma for hematocrits below 40%, with top yields of 20 to 30ml/min) and the efficiencies of these systems are even lower for donorshaving normal hematocrit levels (37 to 47 for females and 40 to 54 formales). The technique, sometimes used, of diluting blood tosubstantially lower hematocrit levels by the use of anticoagulants, isundesirable both for the collected plasma and for the donor.

Much attention has been paid to the shear rate and a number of low sheardevices (below 1000 sec⁻¹) of large area are now in use. These deviceshave been described by workers such as Werynski et al in an articleentitled "Membrane Plasma Separation--Toward Improved ClinicalOperation" Trans. Am. Soc. Art. Int. Organs, 27: 539-42 (1981), andSchindhelm et al in "Mass Transfer Characteristics Of Plasma FiltrationMembranes" published in Trans. ASAIO, 27: 554-8 (1981). The articlesindicate that the low shear systems, typically with shear rates of 500sec⁻¹ or less, are limited primarily by concentration polarization. Atthe opposite limit, for high shear devices (e.g. greater than 2000sec⁻¹) as discussed in detail by Blatt, cited above, deposition is thelimiting factor. This conclusion is supported by an article by Castinoet al in Publication No. 395, Blood Research Laboratory, AmericanNational Red Cross, (also published as Final Report N/A BL Contract No.1-HB-6-2928) entitled "Microporous Membrane Plasmapheresis", by anarticle entitled "Continuous Flow Membrane Filtration Of Plasma FromWhole Blood" by Solomon et al in Trans. ASAIO, 24: 21 (1978), by U.S.Pat. No. 4,191,182 to Popovich, and by U.S. Pat. No. 4,212,742 toSolomon.

Despite widespread and intensive study of high shear systems, however,there has been little commercial use thus far, and upon analysis thisappears to be due to a number of conflicting factors. A reasonableplasma recovery (e.g. 75%) demands excessive membrane area because,among other things, as hematocrit increases plasma flux efficiencyfalls, while blood viscosity increases substantially. To overcome thesefactors by increasing shear would require overly high blood flow ratesobtained, as in Castino or Solomon cited above, by recirculating theblood. Also excessively small gap dimensions would be needed along withobligatory high transmembrane pressure due to blood flow resistance.Such systems are thus inherently limited in capability while the lowshear high area systems are expensive when adequately sized.

After extensive work on and analysis of blood separation problems,including plasma collection, applicant has devised a blood separationtechnique in which a rotary concentric membrane structure impartsangular velocity to the interior surface of an annular blood volumebounded closely on the opposite side by a concentric stationary wall.Remarkable improvements are achieved in terms of plasma recovery rates,plasma purity, independence from hematocrit level, speed of operationand cost. The system and method drastically differ from both thecentrifugation and the membrane filtration techniques previouslyutilized in this field.

Subsequent to applicant's discoveries and development work, applicanthas undertaken a broad search of the patent and scientific literature inorder to acquire a more comprehensive understanding of the relationshipof his system to apparatus and methods used in other fields. Asignificant number of disclosures have been found which spin a rotatablefilter drum or cylinder within a bath of a liquid system in which othermaterial (e.g. sediment or particle matter) is entrained or suspended.The spinning is used to throw off higher density particulates andsuspended matter that impinge upon and plug the filter. The followingpatents comprise examples of this approach:

    ______________________________________                                        U.S. Pat. No. 1,664,769                                                                          Chance     1928                                            U.S. Pat. No. 2,197,509                                                                          Reilly et al                                                                             1940                                            U.S. Pat. No. 2,398,233                                                                          Lincoln    1946                                            U.S. Pat. No. 2,709,500                                                                          Carter     1955                                            U.S. Pat. No. 3,355,382                                                                          Huntington 1967                                            U.S. Pat. No. 3,491,887                                                                          Maestrelli 1970                                            U.S. Pat. No. 3,568,835                                                                          Hansen     1971                                            U.S. Pat. No. 3,821,108                                                                          Manjikian  1974                                            U.S. Pat. No. 3,830,372                                                                          Manjikian  1974                                            U.S. Pat. No. 3,833,434                                                                          Gayler     1975                                            ______________________________________                                    

There have also been various investigations in other fields of the useof a rotating filter member in conjunction with an outer wall forpurposes of imposing shear, examples of which are as follows:

"Description of a Rotating Ultrafiltration Module", B. Hallstrom et alin Desalination (Netherlands) Vol. 24, pp. 273-279 (1978).

"Ultrafiltration at Low Degrees of Concentration Polarization: TechnicalPossibilities", M. Lopez-Leiva in Desalination, Vol. 35, pp. 115-128(1980).

These two publications relate to the handling of solutions, rather thansuspensions, and induce shear solely for specific purposes, such asreverse osmosis. Centrifugation is not an operative factor in thesesystems.

The patents and publications listed above are derived from a widespectrum of arts and technologies which are often nonanalogous, even toeach other. They primarily deal with stable liquid systems which can betreated strenuously without harmful effects. The teachings of thesedifferent publications thus cannot be translated to the myriad problemsinvolved in the separation or fractionation of blood constituents. Thedanger of trauma, the particular adherent qualities of blood, and thesignificant changes in properties that arise as a separation processproceeds all characterize blood fractionation problems as not onlycritical but in fact unique.

Applicant also points out that the broad field of blood processingincludes oxygenation techniques, and that some oxygenation systemsincorporate rotating membranes, as described in:

"An Experimental Study of Mass Transfer in Rotating Cuvette Flow withLow Axial Reynolds Number" by Strong et al. in Can. Jnl. of Chem. Eng.,Vol. 54, pp. 295-298 (1976).

    ______________________________________                                        U.S. Pat. No. 3,674,440                                                                          Kitrilakis 1972                                            U.S. Pat. No. 3,183,908                                                                          Collins et al                                                                            1965                                            U.S. Pat. No. 3,026,871                                                                          Thomas     1962                                            U.S. Pat. No. 3,771,658                                                                          Brumfield  1973                                            U.S. Pat. No. 3,771,899                                                                          Brumfield  1973                                            U.S. Pat. No. 4,212,741                                                                          Bromfield  1980                                            ______________________________________                                    

These patents illustrate some of the special care and expedients thatmust be employed in handling blood, but they propose and utilizetechniques which have previously been considered inimical to bloodseparation objectives, such as flow vortices and other non-laminareffects.

SUMMARY OF THE INVENTION

The Invention provides a system for separating filtrate from a fluidsuspension having at least one biological cellular component using aseparation device that rotates a microporous membrane to inducetransport of the cellular component from the membrane while the fluidsuspension is transported to the membrane.

Systems and methods in accordance with the invention for separatingconstituents of blood subject a thin flow sheet of blood to force for asufficient time to create a concentration gradient of blood constituentswhile concurrently establishing high shear across the sheet. A movingmembrane in contact with the flowing blood and concentric with aspinning axis generates both centrifugal force and high shear on theblood flow through viscous drag. The membrane concurrently filters thedesired medium solely from the adjacent flowing mass. Radial migrationof cellular matter outwardly causes replenishment of lighter filtrate atthe membrane surface to maintain the concentration gradient despiteconstant recovery of filtrate. The thin flow sheet is configured as anannulus between rotating member, concentric about a central axis, and astationary concentric shear wall, and moves longitudinally between entryand exit regions as well as circumferentially about the member. Thefiltrate, essentially free of higher density constituents, passesreadily through the membrane and via the interior of the rotating memberinto an outflow path. This action increases filtrate recovery for agiven membrane area by more than an order of magnitude while virtuallyeliminating deposition and concentration polarization limitations. Lowcost disposables in accordance with the invention process whole bloodfrom a donor continuously without damaging the fragile unstable, bloodsystem. Furthermore, the inlet and outlets are fixed elements and theinternal flow paths are such that the flow paths are sterile and notsubject to external contamination.

Usage of a rotating concentric filtration membrane that is bounded by aconcentric shear wall is applicable to a number of systems forseparating liquid suspensions. High rotational rates in association withsmall gaps generate flow in which a radial concentration gradient andhigh shear are both obtained.

As the following description demonstrates, the invention serves tofilter blood without damage to red blood cells, leukocytes, orplatelets. It is well known that these cellular components of blood areenclosed only by an outer phospholipid bilayer membrane that is notrigid and that can be ruptured relatively easily by mechanical forces.It is also well known that the same type of membrane structure, havingsensitivity to trauma, is common to a large class of biological cells,including all animal cells, such as human blood and tissue cells andvertebrate and invertebrate blood and tissue cells.

The effect becomes noticeable for blood when the rotational rate, theviscosity of the liquid complex, the residence time in the annularseparation zone, i.e. the concentric gap within which the blood flow isconfined, establish conditions within the system with shear in excess of1000⁻¹, and centrifugal forces at the membrane surface of greater than50 gravities (g's). The permissible operating regimes are stable, butrelatively narrow, for blood. For separation of plasma, for example,superior results in terms of cost-performance characteristics areachieved by using small membrane area in a low cost disposable module.In one practical example, using a 2.54 cm (1") diameter spinner and a 50cm² membrane area, a gap dimension of 0.06 cm (0.024") to 0.09 cm(0.037") is employed with rotational speeds of about 3600 r.p.m. Undersuch conditions, and with normal blood viscosity typical of 45hematocrit blood, the shear is in a safely conservative range of 8000sec⁻¹ or less, and residence time and dynamic forces are sufficient forgreater than 90% recovery of pure plasma from a blood flow rate of 60ml/min to about 78% recovery from a flow of 100 m/min. Thus numerous,often conflicting requirements are concurrently satisfied: shear must behigh enough for efficient filtration but not so high as to damage redcells or other matter; dynamic forces must be adequately high toseparate different density constituents without inducing excessiveshear; filtration efficiency must not deteriorate substantially withtime; the residence time must be adequate for high recovery; and thechanging viscosity of the blood stream cannot cause a local variationfrom these conditions.

In a more specific example of a system for separating constituents ofblood, a central spinner may be disposed along a vertical central axis,within an outer confinement vessel whose inner wall defines a shear wallthat is concentric with and spaced apart from the spinner surface by theshear gap. The spinner body includes surface grooves communicatingthrough interior passageways with a central plasma manifold or conduit,and the spinner surface is covered by a membrane having a pore sizeselected for the desired filtrate, such as 0.4 to 0.8 μm for plasma. Thespinner is rotated at the desired rotational velocity as blood is fedtangentially inwardly into the gap. The lower density filtrate passesthrough the membrane pores under transmembrane pressure established bystatic pressure within the system, with filtration efficiency beingmarkedly augmented by high shear. Constituents filtered through themembrane are collected within the interior of the spinner at a centralmanifold and passed out via a central orifice in the rotary seal at thelower end of the chamber. High density constituents move longitudinallydownwardly under flow pressure and gravity to pass out of the shear gapregion directly into a tangential exit orifice. The spinner isindirectly driven by a magnetic coupling at the upper end from anexterior motor driven structure to a magnetic ring on the spinner body.The exterior and interior magnetic elements of the drive coupling may belongitudinally displaced so that magnetic forces constantly exert adownward force on the spinner body, seating it firmly against the rotarybottom seal. The seal functions only to separate the blood and plasmasides of the membrane, and the sterility of the blood path therefore isnot dependent on seal operation. Alternatively the magnetic elements canbe centered so that the spinner is suspended in the magnetic field, andthe seal can be established about the bearing circumference. Thelongitudinal ends of the spinner body are juxtaposed closely adjacent tothe confinement vessel end walls, and air within the system is stablytrapped in small volumes having limited gas-liquid interface area thatisolate the rotary bearings at each end of the spinner. Those parts thatcontact blood, such as the spinner body and confinement vessel, may beof molded plastic and of small size, and of low cost because expensiverotary bearings and seals are not required. Consequently the unit apartfrom the external magnetic drive is a disposable which can be used witha single donor, to collect plasma and return undamaged high hematocritsuspension.

According to an aspect of the invention, the filtration system includesinput pumping means for delivering cellular suspension from a sourceinto the membrane separation device. Outlet pumping means discharges thecellular suspension from the membrane separation device chamber withoutrecirculation. Control means interconnects the input pumping means andthe output pumping means for maintaining a selected flow relationshipbetween the input and output pumping means to obtain a desiredproportion in the input fluid flow rate in relation to the output fluidflow rate. The control means maintains a desired optimal filtrate flowrate while the cellular suspension proceeds in a single pass through themembrane separation device.

The capabilities of systems in accordance with the invention may beutilized to great advantage in blood fractionation systems. In thecollection of plasma, for example, the membrane area can be a smallfraction of the area of membranes currently used, while providing arecovery efficiency, i.e., percent of inflowing plasma componentactually recovered, in the range of 80% to 90% and recovery completionswithin times compatible with the rates at which blood can be taken froma donor. Furthermore the system can function substantially independentlyof the age and hematocrit of the blood being processed. The concepts ofthe invention include not only plasma separation apparatus and methods,but disposable filtration units, and instrumented plasma collectioncontrol as well.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the invention may be had by reference to thefollowing description, taken in conjunction with the accompanyingdrawings, in which:

FIG. 1 is a perspective view, partially broken away, of a plasmacollection apparatus in accordance with the invention;

FIG. 2 is a side sectional view of the apparatus of FIG. 1;

FIG. 3 is a top sectional view of the apparatus of FIG. 1, taken alongthe line 3--3 in FIG. 1 and looking in the direction of the appendedarrows;

FIG. 4 is a top sectional view of a portion of the apparatus of FIG. 1,taken along the line 4--4 in FIG. 1 and looking in the direction of theappended arrows;

FIG. 5 is a graph of plasma flow per unit area as the ordinate vs. bloodflow per unit area as the abscissa for different values of shear insystems in accordance with the invention;

FIG. 6 is a graph depicting the relationship between shear and Reynoldsnumber for different values of rotational rate as the ordinate and gapas the abscissa relative to the arrangement of FIG. 1;

FIG. 7 is a perspective view, partially broken away, of a variation ofthe system of FIG. 1, useful for washing a concentrated red cell mass ofaccompanying white cells and toxic anti-freezing solution;

FIG. 8 is a side sectional view of the arrangement of FIG. 7;

FIG. 9 is a combined schematic and block diagram representation of afirst control and instrumentation system for plasmapheresis inaccordance with the invention; and

FIG. 10 is a combined schematic and block diagram representation of adifferent system for plasmapheresis in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

A blood fractionation system 10 in accordance with the invention,referring now to FIGS. 1-4 extracts plasma from whole blood quickly andat low cost in the quantities typically derived from an individual humandonor. Only the plasma separation device and the associated drive unitare shown, for ease of understanding, although an associated control andinstrumentation system is described hereafter. It should particularly benoted, however, that the system meets the need for a disposable modulethat is so low in cost that it need be used only once. In these Figures,relative sizes cannot be depicted with clarity and it should beexpressly recognized that the drawings are not to scale. Gap sizes andmembrane thicknesses particularly are exaggerated for betterunderstanding.

The system 10 includes principally a generally cylindrical housing 12,mounted concentrically about a longitudinal, vertical central axis, andan internal rotary spinner 14 also mounted concentric with the centralaxis and rotatable concentrically within the cylindrical housing 12. Theboundaries of the blood flow path are defined by the interior surface ofthe housing 12, and the exterior, spaced apart, surface of the rotaryspinner 14, the spacing between which is sometimes referred to as theshear gap for this example. Whole blood is fed from an inlet conduit 20through an inlet orifice 22 which directs the blood into the blood flowentrance region in a path tangential to a circumference about the upperend of the rotary spinner 14. The inner wall 24 of the housing 12 liesin a right circular cylinder spaced at a uniform distance, hereapproximately 0.024" (0.06 cm) from the outer circumference of therotary spinner 14, which also is a right circular cylinder in thisexample. At the bottom end of the cylindrical housing 12 the housinginner wall includes an exit orifice 34, the outer edge of which liesalong a tangent to an interior circumference within an exit region atthe lower end of the shear gap. At the tangents along which the inletorifice 22 and exit orifice 34 lie, the circumferential flow velocityabout the spinner 14 substantially matches the input and output flowrates to reduce acceleration and deceleration effects in an optimizeddesign. However, practical systems that have not used this optimizedmatching of velocities have not been observed to have deleteriouseffects on the blood.

As seen only in the sectional view of FIG. 3, the inlet flow of bloodpasses first through a converging section 26 and then through a straightsection 28 having a length at least five times as great as thecross-sectional dimension of the inlet orifice 22. The exit orifice 34couples to a curved diverting channel 36 (FIGS. 3 and 4 only) which isso shaped as to avoid the introduction of a curvature of opposite senseto the flow within the housing 12, thus providing an alternative exampleof the manner in which flow may be achieved for either inlet or outletorifices. The width of the orifice should not exceed the gap dimension.The orifice dimension in elevation, however, may be made substantiallylarger than the gap dimension in order to adjust inflow velocity orincrease scavenging efficiency at the outlet. The inlet flow sections26, 28 and outlet channel 36 may be molded, in part, with the housing 12and completed by complementary halves which are affixed thereto.

The cylindrical housing 12 is completed by an upper end cap 40 having anend boss 42, the walls of which are nonmagnetic, and a bottom endhousing 44 terminating in a plasma outlet orifice 46 concentric with thecentral axis. The rotary spinner 14 is mounted in a vertical positionbetween the upper end cap 40 and the bottom end housing 44. The spinner14 comprises a shaped central mandrel 50, here 1" (2.54 cm) in diameter,preferably of a light weight, strong, impermeable synthetic resinmaterial such as high density polypropylene. To simplify molding it maybe made in two separate pieces (not shown) that are joined together. Theouter surface of the central mandrel 50 is shaped to define a series ofspaced apart circumferential grooves 52 separated by annular lands 54which lie uniformly in the plane of the cylindrical outer periphery ofthe mandrel 50. The surface channels defined by the circumferentialgrooves 52 are interconnected by four longitudinal grooves 56 regularlyspaced in quadrants about and extending almost the entire length of themandrel 50. At each end of the mandrel 50, these grooves 56 are incommunication with a central orifice or manifold 58 (best seen in FIGS.2 and 3) concentric with the central axis, via one of a set of fourradial conduits 60 disposed in the same quadrant positions. The grooves56, orifice 58, and conduits 60 are of sufficient cross-sectional areato avoid imposing a restriction on the flow of filtrate. Also, thecircumferential grooves 52 and longitudinal grooves 56 are large enoughin cross-section so that there is no substantial difference in pressuredrop for fluid regardless of where it transfers through the membrane. Inanother sense, the pressure drop variations should not be more than asensible fraction of the transmembrane pressure for high performanceoperation. Relatively close spacing of the circumferential grooves 52also is desirable for this uniformity. Two longitudinal lands 61 extendalong the mandrel 50 in symmetrical spacing to the longitudinal grooves56. Thus the mandrel 50 is inherently balanced about its central axisand may be spun at high speed without instability.

The surface of the rotary spinner 14, which is about 3" (7.5 cm) inlength, is covered by a cylindrical membrane 62, such as a commerciallyavailable filtration membrane of the type sold under the designationpolyvinylidine fluoride by Millipore. The membrane 62 has a nominal poresize of 0.6 μm, but other pore sizes may alternatively be used (therange for plasma typically being 0.4 to 0.8 μm). The total surface areaof the cylindrical membrane, in this example, is approximately 50 cm²,which is substantially more than an order of magnitude less than themembrane surface area utilized in prior art systems for recovering about30 to 50 ml/min of plasma.

At its upper end, the rotary spinner 14 is mounted in the upper end capto rotate about a pin 64 which is press fit into the end cap 40 on oneside, and seated within a cylindrical bearing surface 65 in an endcylinder 66 attached to or forming an integral part of the rotaryspinner 14. The lower end of the pin 64 protrudes into a small chamberadjacent the bearing surface 65 so that the pin end does not dig intothe end cylinder 66. The end cylinder 66 is partially encompassed by aring 68 of magnetic material (e.g. 440 C. stainless steel of Rockwellhardness 45 to 50 or a molded ceramic magnet) utilized in indirectdriving of the spinner 14. For this purpose, a drive motor 70 exteriorto the housing 12 is coupled to turn an annular magnetic drive member 72which partially surrounds the nonmagnetic end cap 40. The drive member72 includes at least a pair of internal permanent magnets 74 in spacedapart, facing relation to the magnetic ring 68 in the end cylinder, butcentered below the midpoint of the ring 68 along the vertical centralaxis. As the annular drive member 72 is rotated, magnetic attractionbetween the ring 68 interior to the housing 12 and the magnets 74exterior to the housing locks the spinner 14 to the exterior drive,causing the spinner 14 to rotate without slippage. Moreover, thevertical displacement between the magnets 74 and ring 68 imposes aconstant downward force on the spinner 14. A rotational speed of 3600r.p.m. is used in this example, although significantly higher rotationalrates can be used where other parameters are varied or where there isless concern with a minor amount of hemolysis. The given configurationmay be operated up to 5550 r.p.m., for example, without substantialhemolysis. Belt drives or gearing (not shown) coupled to the drive motor70 may be used to step up the rotational speed of the spinner from thenominal rotational rate of the motor 70.

At the lower end of the rotary spinner 14, the central outlet orifice 58communicates with a central bore 76 in an end bearing 78 concentric withthe central axis. The end bearing 78 is seated in the bottom end housing44 and includes an intermediate tapered side surface 79 that diverges inthe downward direction. An end bearing seat is defined by a narrowedconcentric throat or internal shoulder 80 forming the lower edge of acentral opening 82 in the lower end of the bottom end housing 44. Wherethe material of the spinner 14 is too soft or yielding, wear at thebearing 78 may be excessive or the seal might otherwise becomeinadequate for the entire duration of use. In such event a small insert(not shown) of the same internal profile but of harder material may beinset into the spinner 14 in this region to insure maintenance of theseal. End seals or O-rings (not shown) might alternatively be used toprovide thrust bearing seals.

The central opening 82 communicates with the plasma outlet orifice 46. Aradial bearing surface is defined by the cylindrical upper portion 83 ofthe end bearing 78, which fits within a mating surface of the centralopening 82. As the spinner 14 rotates the end bearing 78 is mechanicallyurged downwardly on the shoulder 80 region by the magnetic coupling,forming an end seal. If wear occurs the integrity of the seal ismaintained, although a properly configured device has a much longeruseful life capacity, in terms of wear, than will be required inpractice.

The lower end of the spinner 14 body also includes a concave surface 84facing the opposing end wall, to increase the volume about the endbearing 78. This configuration at the lower end of the spinner aids thecapture of entrained air and the formation of a stable bubble about thelower rotary seal to enhance the integrity of the seal and limit heattransfer to the blood flow that might contribute to hemolysis. Minimumblood-air interface areas exist at both ends of the housing 12, whenbubbles are trapped at these regions, because the longitudinal ends ofthe spinner 14 are disposed close to the adjacent end walls (e.g. hereless than 0.02" (0.05 cm). The concave surface 84 need not be employed.In addition the reduced diameter of the end cylinder 66 relative to thespinner 14 aids both in the capture of air and in the reduction of gapsize without increasing shear stress on the blood. Turbulence in the endregions can induce hemolysis into the plasma retained in the blood flowmass and intensify sealing problems.

In operation, with the rotary spinner 14 rotating at the 3600 r.p.m.rate chosen in this practical example, whole blood is fed through theinlet orifice 22 in a low acceleration and deceleration flow path thatcommences with tangential entry into the shear gap between the outersurface of the spinner 14 and the inner wall 24 of the housing 12.Circumferential velocity is imparted by viscous drag on the blood layerthat is in contact with the outer cylindrical membrane 62 on the rotaryspinner 14, so that the spinning action creates a flow about and withthe spinner 14.

Ingress of whole blood is preferably at a rate matching the averagecircumferential velocity in the region of the inlet orifice 22, so as toavoid abrupt shock and sudden acceleration. Although matching of bloodinlet flow in this manner is desirable, it is not necessary to maintaina precise relationship because in practice no adverse effects have beenobserved with a range of inlet flow rates and geometries inplasmapheresis systems of the general character of FIG. 1. The action ofviscous drag then provides acceleration, without damage to the blood.Stabilization is quickly achieved as the internal volume between theinner walls of the housing 12 and the outer surface of the rotaryspinner 14 is filled. Prior to stabilized operation and plasma outflow,air in the system is forced out through the membrane 62, moving rapidlyinwardly through the circumferential grooves 52, the longitudinalgrooves 56 and the radial conduits 60 to the central bore 76 in the endbearing 78 to the plasma outlet orifice 46. Plasma immediately begins tofollow. The flow of blood may be preceded by a small volume of salinesolution in the operation of an integrated system. Centrifugal forcesare kept above 50 gravities at an approximate minimum and below 445gravities at an approximate maximum for the stated configuration andoperating conditions. These are not fixed limits, however, inasmuch asflow rates, residence times, and other parameters may be varied forparticular applications. For example, if the centrifugal force islowered below 50 gravities the throughput rate will be reducedsignificantly but can still be advantageous. Concurrently, the entirecylindrical shell of blood moves longitudinally downward at essentiallyconstant velocity in the shear gap. These conditions alone do not assurehigh efficiency filtration or non-traumatic handling of blood.

The critical and unstable characteristics of blood arise from bothchemical and physical factors, and disruptive effects can easily occurin a high speed, high shear system. Blood has a tendency to adhere toand cover surfaces having foreign characteristics, unless propermovement is maintained. Normal whole blood has a hematocrit of 37 to 54with a viscosity (μ) in the range of 4 to 5 centipoise at a density (ρ)in the range of 1.0 grams per centimeter³. The viscosity of the flowduring plasmapheresis, however, markedly increases, because the mass offormed elements without substantial plasma, and particularly the redcell pack, is thixotropic in character. Maintenance of proper flowconditions for these and other reasons, involves due attention to all ofthe parameters affecting the separation of blood.

The inflow rate of the blood (here about 60 to 100 ml/min) and theinternal volume available for blood flow, determine the residence timeof the blood within the system. The residence time is typically of theorder of 3 seconds in the given example. In one practical system, with aspin rate of 3600 r.p.m., a diameter of 1" (2.54 cm) for the cylindricalmembrane 62, and a radial gap of 0.024" (0.06 cm), a shear level ofabout 8000 sec⁻¹ and a centrifugal force of 190 gravities are imposed onthe blood passing through the shear gap region. Thus in accordance withthe shear principles previously discussed, platelets, leukocytes andother formed elements in the blood are kept in motion across themembrane surface and do not tend to adhere to or plug the pores of themembrane as plasma passes through. It is of significance, relative toeffective use of the shear principle, that high shear rates are createdwithout involving either the very small gapes or excessively high flowor recirculation rates normally accompanied by concomitantly high flowresistance, as used in the prior art. Cell packing and concentrationpolarization, normally present in other systems, are obviated and haveminimal effects on the membrane filtration action. In fact, it has beenfound that even though pinholes may exist in the membrane noticeable redcell concentration or hemolysis is not present in the plasma outflow.The efficiency of plasma transport through the membrane 62 is extremelyhigh throughout an entire cycle of operation. The sole source of thetransmembrane pressure in this instance is the static pressure withinthe system, inasmuch as the velocity components induced by viscous dragtend to oppose the inward motion. Nevertheless, static pressure of theblood flow itself is adequate not only to provide the neededtransmembrane pressure, but to cause flow of the plasma filtrate intothe surface channels defined by the circumferential grooves 52, fromwhich the plasma is collected into the central orifice or manifold 58via the longitudinal grooves 56 and the radial conduits 60.

Plasma flow from the system is derived at a rate of about 45 ml/min inthis example, given a blood flow of approximately 100 ml/min dependingon hematocrit, thus being consistent with the rate at which whole bloodmay be taken from a donor and the packed cell mass with residual plasmamay be returned to the donor.

Recoveries in excess of 90% of plasma have been achieved. FIG. 5 showsactual performance results in which attainable quality plasma flux perunit membrane area has been plotted against blood inflow rate similarlynormalized. The initial slope of all curves is determined by the inletblood hematocrit. Therefore, in order to put a great many experimentaldata taken from various runs with different blood sources on a commonplot all data has been corrected to the typical 45 hematocrit where theinitial slope is theoretically: ##EQU1## where P=plasma rate

B=inflow blood rate

Am=membrane area

Note that plasma rates become asymptotic with increasing blood flowalthough the level of the asymptote increases with increasing r.p.m. asexpected. Theoretical prediction of the asymptotic value is difficult.It has been empirically demonstrated, however, that the value increasesmore rapidly as a function of centrifugal force (when shear rate is heldconstant by varying the gap spacing proportionately with r.p.m.) than itdoes for increasing shear with constant centrifugal force (by varyingthe gap only). In either case, those skilled in the technology willrecognize that the current state of the art provides plasma recoveries,per unit of membrane area, that are usually less than 0.05 ml/min-cm².In the current art, flat plate systems are producing, at best, about 55ml/min with a 1400 cm² membrane area (0.039 ml/min-cm²), while hollowfiber systems are producing about 22 ml/min with a 1700 cm² membrane(0.013 ml/min-cm²). In contrast, with the 1" spinner, 50 cm² membraneand the shear gap and rotational rate of the system of FIGS. 1-4, theflow rate is easily stabilized at about 0.9 ml/min-cm² and can be takenhigher. Applicant has thus provided, approximately an order of magnitudeimprovement over prior techniques used in this intensely worked art.

Systems constructed in accordance with the invention and used togenerate the performance data of FIG. 5, provide a plasma filtrate thatis protein rich, golden in color, and essentially completely free ofhemolysis and any trace amounts of formed elements. The hematocrit ofthe packed cell mass that moves out of the exit orifice 34 is in therange of 75 to 90% and exhibits only minimal if any increment of freehemoglobin over normal biological levels. The dual capability for highefficiency recovery of plasma and the return of high hematicrit flow toa donor will be recognized as extremely significant by those skilled inthe art.

The extremely low blood priming volume, achieved by virtue of very lowmembrane area together with small blood film thickness, will beappreciated as a significant medical advantage in certain therapeuticapplications of the device. In the example of a practical device thetotal hold-up volume of the device including entrance orifices andheaders, but excluding the remainder of the blood lines and bags, isonly approximately 5 ml in the collection device.

Further, the cost savings inherent in using a small area of expensivemembrane are also evident for disposable systems. The problem inplasmapheresis, for the practical application that is described herein,is to transfer a normal donor supply of 2-3 units of blood through asmall disposable unit which will reliably function to recover 60% to 90%of the protein rich plasma and return the high hematocrit flow readilyto the patient without damage to red blood cells, leukocytes orplatelets.

In accordance with the invention, the spinner surface velocity v_(s) andgap (d) are selected, relative to the entering blood viscosity (μ) anddensity (ρ) such that high centrifugal force and shear values areestablished, but (in order to protect red cells) not in excess of 15,000sec⁻¹, and with the Reynolds number being below 2000. Given that:##EQU2## where D is the spinner diameter in inches and the (r.p.m.) isthe rotation rate per minute, ##EQU3##

In the above, μ is in units of poise, d and D are in inches and s_(max)is the maximum value of blood shear rate qualified below. The value ofμ, the coefficient of absolute viscosity, for an "ideal" Newtonianfluid, where viscosity is not a variable, is 0.5. However, because ofthe high viscosity and thixotropic characteristic of blood whereinviscosity varies with shear rate and is an exceptionally strong functionof cell concentration, the velocity profile across the gap between thespinning wall and the stationary wall is not a linear function. It hasbeen determined experimentally that an approximate value of α=0.9 may beused. The significance of Equations (1) and (2) above may then beinterpreted as follows. If one elects the maximum value of (r.p.m.)given by Equation (1) then d is constrained to a single value for whichEquation (2) is an equality. For all lower values of (r.p.m.) theinequalities of Equation (2) permit a range of choices for gap dimensiond.

Following these considerations, and constrained by the practical needfor a small, low cost and disposable spinner, the useful andconservatively safe operating values for critical parameters fall withinrelatively small ranges. Adopting a conservative limit of 12,000 sec⁻¹for shear in order to limit hemolysis to negligible levels for a 1"spinner, for example, the gap between the spinner and the containmentwall in a practical device is 0.155" to 0.037" given a rotational rateof the spinner at 3600 r.p.m., as seen in FIG. 6. For a maximum rotationrate of 5550 r.p.m. the gap dimension is 0.024" and one is operating atthe marginal level at which hemolysis may occur.

Further consideration should be given to the graph of FIG. 6 in terms ofthe interacting relationships that are to be observed with blood as theliquid suspension system. With the gap dimension (d) as the abscissa androtational rate (r.p.m.) as the ordinate, a linear shear line may bedrawn from the common base point for the predetermined maximum shear(s_(max)) that will be tolerated. Lines are shown for shear rates of8000 sec⁻¹, 10,000 sec⁻¹, 12,000 sec⁻¹, and 15,000 sec⁻¹ at the highestof which levels greatest hemolysis occurs, although still found to be atan acceptable level for many applications. Increases in hemolysis arefirst detected at about 12,000 sec⁻¹, but hemolysis is not significantuntil 14,000 sec⁻¹ is reached, and becomes very significant above 15,000sec⁻¹. The linearity of the shear rate follows from the expression forshear previously given, and because the non-linear characteristics donot strongly affect plasmapheresis applications. The slope of the shearline will be substantially steeper for a stable, non-critical liquid.Although as previously noted, the velocity gradient may well not belinear, the non-linearity appears to be operative in a favorable sensebecause the lighter plasma strata appears to be subjected to high shear.There are only minor increases in hemolysis levels, tolerable for manyapplications, when nominal shear rates exceed the approximately 6000sec⁻¹ to 7000 sec⁻¹ limits encountered in the prior art. These lattervalues correspond to the shear stress levels of 240 to 280 dynes/cm² fornormal human blood as reported by Blackshear, P. L. Jr. et al in "FluidDynamics of Blood Cells and Applications to Hemolysis", NTIS ReportPB-243 183, pp. 95-102 (October 1974), see also Chien, S. et al,"Shear-Dependent Deformation of Erythrocytes in Rheology of HumanBlood", Amer. J. Physiol.,V. 219, p. 136 (1970).

There is a generally inverse and non-linear relationship between r.p.m.and d with respect to Reynolds number. For a given viscosity (e.g. bloodat 4 centipoise) a curve of opposite slope representing Re≦2000intersects the shear lines at intermediate points. The r.p.m. valueassumes a certain spinner diameter (here 1") and thus centrifugal force,and it will be recognized that the curves are merely offset by anyadjustment of the spinner size. Although centrifugal force has someinfluence at even low r.p.m. values, practical systems require anoptimum combination of small size, low cost, high recovery of plasma andlimited time demands on the plasma donor. Thus a rotational rate, for aparticular spinner diameter, that is sufficient to give in excess of 50gravities will typically be used in practical systems.

These controlling factors dictate the configuration, throughout theentire length of the device, including entry and exit regions andbecause it is preferred to utilize, for disposable plasma separatorsystems, a compact structure. In a compact structure, however,introduction of blood into the gap region, and extraction of highhematocrit flow at the outlet end are effected by tangential paths whicheither include a stabilizing section or avoid introduction of reversecurvature in the flows. The outlet aperture and the exit region may bemodified in particular ways to accommodate the increased viscosity ofthe thickening flow mass in this region. The outlet aperturecross-section need not be symmetrical, for example, so that area can beincreased by extending the height (elevation) dimension along thecentral axis. Also, the shear gap may be increased, due to theincreasing viscosity of the thickening cell mass near the exit. Thus inthe system of FIGS. 1-4 the gap width may be enlarged in curvilinearfashion, along with or separately from the height, to further increasethe cross-sectional area of the exit orifice and improve scavenging ofred cells.

The length of spinner which is covered by membrane is preferably short,because of the cost of the membrane material. For 50 cm² of membrane,which is sufficient for recovering 20-50 ml/min of plasma from a givendonor, depending upon hematocrit and blood supply rate, the membranecarrying length of a 1" spinner is less than 3". Despite this relativelyshort length, the residence time is fully adequate for high recoveryrates. The example of a low cost disposable given herein processes 3units (1500 ml) of flow to collect 600-700 ml of plasma, thereby givingat least a 75% recovery fraction. The length and total residence timecan of course be increased when desired for particular processes. Inaddition, the blood flow can be pressurized so that transmembranepressure is increased and the filtration process enhanced.

It will be appreciated here that the drawings are not to scale and thatshear gaps, as well as variations in shear gaps, have been depicted onlygenerally to illustrate the principles involved.

The outer wall can serve not only as a stationary shear boundary butalso perform other functions, as depicted in FIGS. 7 and 8. It is not aconventional procedure to preserve frozen concentrated red cells in anantifreeze solution (ethylene glycol) whereby the cells may be frozenbut are protected by the non-frozen liquid matrix from crystallizing andbreaking. The red cells must be washed free of the solution in whichthey are suspended after they are returned to a useful temperaturerange. While the frozen red cells may be stored in a relatively purestate by the use of a pre-filtration process, such procedures aredifficult and expensive. Usually, therefore, the concentrate isaccompanied by white cells and white cell aggregates which adheretogether and form a slimy, floating substance that is colloquiallyreferred to as "snot". Removal of the white cell aggregates along withthe toxic carrier is a prime objective. The fractionation system ofFIGS. 7 and 8 utilizes the basic structure of the system of FIGS. 1-4,but with further features to enable clear separation of concentrated redcells from fall such extraneous matter.

The spinner 14 is driven as previously described, but is somewhatdifferent in interior configuration and in the flow passageway system.The principal length of the spinner 14 is a hollow cylindrical body, theouter wall 90 of which includes circumferential grooves 52 as previouslydescribed, interconnected by two longitudinal grooves 92 of adequatecross-sectional area to permit unimpeded flow. The hollow body mayreadily be fabricated by molding two or more parts that are threaded orbonded together, and represents savings in material as well as mass. Atthe lower end of the spinner 14, each longitudinal groove 92communicates with a short central axial manifold 94 via a differentradial conduit 96. The upper end of the spinner 14 rotates on an axialbearing 98 set into the cylindrical housing 12, and a magnetic ring 100concentric with the central axis is remotely driven as previously. Forhigher torque applications separate elements of high coercivity ceramicmagnet (not shown) may be used instead of the magnetic ring. Thevertical offset between the spinner magnetic structure and theassociated drive is different from the arrangement of FIGS. 1-4, in thatthe outer drive is centrally positioned along the height of the ring100. Thus the biasing force exerted by the magnetic field suspends thespinner 14 between bearings at each end, creating a predeterminedclearance between the lower end of the spinner 14 and the bottomhorizontal inner wall of the housing 12 and eliminating any thrustloads. A rotary seal at the lower end is provided by a radial O-ring 102disposed about an apertured end bearing 104 seated in the housing andseated in a circumferential groove 106 in the side walls of the centralaxial manifold 94. Even though the spinner 14 may slide down relative tothe O-ring 102 prior to installation of the separator device in asystem, the spinner 14 is quickly drawn to and held in the properclearance position by the magnetic biasing force when in operation.

In this example, the spinner 14 is covered with a surface membrane orfilter 108 having a pore size of approximately 70 μm for the passage ofethylene glycol, white cell aggregate and saline solution. A range ofpore (or other aperture) sizes of 60-100 μm is generally suitable forthis application, but can be varied depending on such factors as specialcharacteristics of the flow mass and the percentage of red cells to belost through the filtering element. Where the mass contains no or littlewhite cell aggregate the pore size can be about 0.6 μm, for example. Thecylindrical housing 12 includes a porous cylindrical inner wall 112 atleast coextensive with the length of the membrane or filter 98. It ispreferred to use a porous synthetic material such as sinteredpolypropylene, polyethylene or polytetrafluoroethylene. With larger sizeapertures being usable, however, the wall 112 may alternatively compriseone or more screens of fine mesh, such as stainless steel, or an elementin which apertures have been formed, as by a laser beam. In any eventthe wall 112 has sufficient porosity that a saline solution may permeaterapidly in the desired proportion to the flow volume of the concentratedred cells and accompany matter. This proportion may range from somewhatless than 1:1 to 20:1 for such flow masses. The inner wall 112 isseparated from an outer wall 114 defined by a part of the housing 12,and the intervening space defines a plenum 116 to which is coupled aninlet 117 for saline solution. The inlet flow mass is injected via aninlet orifice 118 into the shear gap between the spinner 14 and theinner wall 112 of the housing 12, and washed red cells are derived atthe lower end of the shear gap at an outlet orifice 119. If desired, thesaline solution flowing into the system may be substantially pressurizedwithin the plenum 116 so as to increase or control the throughput rateof the saline solution.

As the spinner 14 rotates, saline solution constantly permeates in ahigh area cross-flow through the porous wall 112 into the shear gap inwhich the red cells are being spiraled downwardly along with the toxiccarrier and white cell aggregate. Thus at the upper end of the spinner14, concentrated ethylene glycol begins to pass concurrently as filtratethrough the membrane 108 along with gradually increasing amounts ofcross-flowing saline solution. The constant introduction of salinesolution about the outer periphery then acts initially on the leastcontaminated portion of the blood cell mass. As the saline solutionpasses through the entire thin shell flow it intermixes with anincreasing proportion of ethylene glycol and white cell aggregate,acting in a sense as a diluent while also carrying this lighter matterinwardly. Toxic carrier along with white cell aggregate in heaviestconcentration and saline solution is most diluted form encounter themembrane 108 and are filtered out of the system. The relatively largepore size of the membrane 108 permits ready passage of the oleaginouswhite cell aggregate, while the toxic carrier and saline solution arewashed out with even grater facility. A minor fraction (typically lessthan 1-2%) of red cells also may wash out through the large pores, butthis can be accepted in exchange for elimination of the mucous whitecell mass. The cross flow of the purifying saline solution relative tothe spinning cell mass, being distributed across a high area but havingonly a short path length in the radial direction, is thus extremelyefficient. Newly injected saline solution constantly moves across theentire flow area, and there is no possibility of formation of static orstagnant pool of toxic carrier. At the outlet orifice 119, therefore,only purified red cells leave the system from the shear gap region.Typically, the volume of saline solution, per unit volume of incomingcombined red cell, white cell aggregate and ethylene glycol, will besufficient to insure that only a minor proportion of saline solution ispresent in the red cell outflow. If desired, however, the volumetricrelationship between the incoming flow and the saline flow can beadjusted to provide a controlled hematocrit in the red cell outflow.

FIG. 9 is a generalized and schematic representation of a system inaccordance with the invention that provides a completely disposableblood handling set employing a fractionation module 120 based on theshear principle with a single needle implantation device 122, this beingthe instrument of choice for donor comfort in blood fractionationapplications for human donors. All portions of the system which comeinto contact with blood flow, or separated constituents of blood, are oflow cost and disposable character, while blood pumping, sensing andcontrol functions are carried out externally of the distribution system.The fractionation module 120 is simply clamped or positioned in place bya suitable bracket or other means (not shown) on a system console 124,within which motors and instrumentation are mounted, although these areshown in schematic or block diagram form inasmuch as the configurationof the console 124 is not significant for purposes of the presentdisclosure. When in position, the upper end of the module 120 fitswithin a magnetic coupling 126 which is driven by a drive motor 128,thereby to rotate the spinner within the module 120.

Plasma flow from the bottom of the module 120 proceeds through a lengthof flexible tubing 130 to a plasma collection bottle 132, past anoptical hemaglobin detector 134 and a tubing clamp 136. The hemaglobindetector 134 may be any suitable commercially available device that isoptically sensitive to the passage of material having the opticalcharacteristics of hemaglobin in the blood, because the presence of asignificant amount of blood indicates a leakage or failure in thesystem. The detector may generate a signal which activates a display(not shown) for the operator, so that the clamp 136 can be manuallyclosed, or may provide a signal to an automatic system for activatingthe clamp 136 by solenoid control.

At the donor end of the system, the intravenous disposable needle 122couples through a first junction 140 to an inlet blood flow line 142 anda return line 144, both of these lines being of flexible, disposabletubing. The coupling to the inlet blood flow line 142 is made through asecond junction 146, the alternate port of this Y configuration junctionbeing coupled to a third junction 148 which receives saline solution ona saline priming line 150 at one port, and an anticoagulant on ananticoagulant delivery line 152 at the other port. The saline primingline may be closed by the operator at a clamp 154 or automatically ifdesired, when the priming function has been carried out. A source 156 ofsaline solution is gravity fed through a source line 157 to a connector158 which couples both to the saline priming line 150 and to a salineinjection line 160 that is used in a manner described hereafter. Ananticoagulant source 162 also elevated above the system, feeds throughthe anticoagulant delivery line 152, which is of smaller diameter thanthe blood tubing, past a roller or peristaltic pump 164 which isadjustable by a pump control 165 so as to provide a selected rate ofdelivery of anticoagulant, depending upon the hematocrit and blooddelivery rate of the donor. The anticoagulant pump control 165 may beoperator adjustable, although a microprocessor controlled system mayalso be utilized, including means for sensing blood flows at variouspoints and adjusting the rate of anticoagulant delivery within limits soas to maintain the blood flow. The donor and implanted needle 122 shouldalso be understood to be physically elevated with respect to the system,so that blood flow on the inlet line 142 is initiated and at leastpartially maintained by gravity in order to protect the donor fromsuction at the vein.

The inlet blood flow line 142 passes a pressure transducer 166 which isof the type that has a sterility barrier and senses pressure variationsin the flexible tubing without occluding the line or introducing aseparate flow path. The pressure transducer 166 generates a signal whichcan be utilized to control an analog display for the operator, becausethe lack of pressure in the system, once started, may indicate adeleterious condition such as displacement of the needle or suction onthe line.

The inlet blood flow line passes a roller pump 170, depictedschematically, which is set to an adjustable rate by a blood flow pumpcontrol 172, and terminates at the inlet orifice to the fractionationmodule 120. The same roller pump 170 also is in operative associationwith a blood outflow line 174 which passes via a Y junction 176 and thepump 170 to a reservoir 180. The reservoir 180 is a flexible disposablecontainer including a bottom outlet to which the blood return line 144is coupled, and is interposed between a pair of movable platens 182,183. The platens 182, 183 are movable transversely outwardly in oppositedirections against springs 184, 185 as the reservoir 180 fills withblood, because a clamp 186 on the return line 144 blocks outflow fromthe reservoir 180. When the reservoir 180 is sufficiently filled, alimit switch 187 is actuated by the adjacent platen 183 to indicate thatthe cell flow is to be returned to the donor. This may be done manuallyby an operator in response to a signal or display, by stopping the pump170 and releasing the clamp 186, or the actions may be undertaken by anautomatic control system coupled to the blood flow pump control 172 anda clamp control 188. A separate limit switch 189 is positioned to detectwhen the platens 182, 183 have moved inwardly together to the oppositelimit position and have expressed all or substantially all of the returnflow to the donor. The springs 184, 185 are depicted only generally, andit will be understood that they may be of the type that providessubstantially constant and relatively low force throughout the length oftheir travel, thus insuring gentle and hemolysis-free return of blood tothe donor. Alternatively, a mechanical, pneumatic or hydraulic devicemay be used for this purpose. It will also be appreciated that thereservoir 180 may include a manually or automatically closeable vent(not shown) for allowing the escape of air from the device. A separatordevice 192, such as a wedge in the simplest case, is movable manually orautomatically between the platens 182, 183 to separate them slightlyfrom the fully closed position.

In operation of the system of FIG. 9, priming of the lines is aconventional safeguard that precedes actuation of the blood flow pump.With the spinner in the fractionation module 120 operating, however, thepump 170 may be turned on after priming, to begin the inlet flow ofblood, accompanied by a suitable amount of anticoagulant from the source162, the amount being related to the volumetric flow of the plasmaportion of the total blood flow and being a fraction thereof. With therate of plasma delivery from the donor of 30 to 50 ml per minute, atypical plasma volume of approximately 600 ml is collected in 10 to 20minutes. The hematocrit of the donor, as well as the donor size andweight, and other factors, however, establish that the blood flow rateand plasma contributions of individual donors can vary substantially.Consequently, it is not safe to assume that a specific proportion ofreturn flow exists in relation to the whole blood inlet flow or theplasma extracted. Furthermore, pulsations that tend to be introduced bya roller pump can tend to cause surges within the fractionation module120, or a momentary disparity between inflows and outflows that causescellular matter to penetrate through the membrane in the module. Suchproblems are avoided by the usage of the blood flow pump 170 to controlboth blood inlet and blood outlet flows, in addition to supplementationof the outlet flow with saline solution via a saline pump 191, the rateof operation of which is adjustable by a saline pump control 192. Theroller pump 170 is preferably of the type having a pair of opposedrollers, symmetrically displaced with respect to the lines 142 and 174respectively, so that each roller engages and disengages the associatedline at a given point in time concurrently. Thus, the pulsations whichoccur upon engagement appear at both the entry and outlet ports of themodule 120 and no excess transmembrane pressure appears in the flow ofplasma. The coordinated action in effect eliminates pulsations on themembrane at times of momentary interruptions of flow. Consequently thereis positive displacement of both inlet and outlet flows, and because thepumping actions are physically determined by the geometry of the rollerpump 170, no compensating features need be employed. Furthermore, anydifferential in the amount of plasma fraction that is extracted at themodule 120 can be safely compensated by the injection of saline into thereturn cell flow. The operator can use the saline pump control 192 tomake adjustments in the net rate of the pump so as to limit the maximumoutput of plasma to a safe level. The pump 170 tends to displace thesame volume of outflow solution as inflow solution, for a givenrotation, or to displace a fixed proportion other than 1:1 if the tubingsizes are different. The volume of saline made available per revolutionis directly translatable to mass, and this replenishment enables preciseand reliable control of the amount of plasma that can safely be takenout of the system. A pump, such as the roller pump 170 is advantageouslyemployed for varying the rate of saline injection, but it will also beappreciated that the size of the saline line may also be varied to givea proportional control, with or without the use of the pump 170.

The return flow is not continuous, but only takes place when apredetermined maximum level of blood in the reservoir 180 has beensensed by the limit switch 187. At this time, the blood flow pump 170 isstopped, the clamp 186 is opened, and the platens 182, 183 are thusfreed to compress the reservoir 180 gradually. This compression returnsthe cell mass with saline solution through the return line 144 to thedonor at a higher rate, such as 100 to 300 ml per minute. Beforeresuming inlet flow it is advantageous to separate the platens 182, 183slightly and momentarily with the separator device 190, which in thesimplest case may be a wedge interposed between the platens 182, 183.Release of pressure on the reservoir 180 causes a small amount of thepacked cells to be drawn backwards into the reservoir 180, to draw donorblood past the junction 140 so that blood cell remainder is kept frombeing fed into the module 120 on the inlet line.

It will be appreciated that additional blood flow reservoirs may beutilized, if desired, and that different pumping systems may beemployed, particularly where the requirements of a single needle,disposable blood set application need not be met.

An example of one such system is shown in FIG. 10, in which elements anddevices are numbered as in FIG. 9 and only system variants are shown,with most of the duplicative portions being omitted for brevity. In FIG.10 the blood outflow line 174 feeds blood cell remainder into atransparent or translucent reservoir 193 having a top vent 194 and abottom outlet to which the blood return line 144 is coupled. A leveldetector 195 disposed adjacent the reservoir 193 provides an analogsignal to a return pump control 196 which actuates a return roller pump197 to rotate it in the proper direction (counterclockwise) to returnthe cell flow to the donor. The return pump control 196 may also berotated in the opposite direction (clockwise) when blood or salinesolution has reached the pump 197 through the return line 144 duringpriming operations. This rotation feeds solution into the bottom of thereservoir 193 and dispels air from the return line 144 so that there isno danger of returning an air bubble to the donor. A separate blood flowpump 200 and associated control 202 are used at the inlet side of themodule 120, while a separate outflow pump 204 and coupled control 206are used at the outlet side. The two pumps 200, 204 are operated in aselected flow relation (which may be operator or microprocessorcontrolled) the difference being the plasma flow rate. When thereservoir 193 is filled to a selected level, the signal from the leveldetector 195 permits manual or automatic stoppage of the pumps 200, 204,and actuation of the return pump 197, until the reservoir 193 contentsare returned to the donor. When delivery is complete, momentary reverseactuation of the return pump 197 can be employed to withdraw blood cellremainder from the needle 122 into the return line 144, so that onlywhole blood passes to the module 120 via the inlet blood flow line 142.Such an arrangement may be used where it is preferred to limit dilutionof the plasma protein content by avoiding return of saline solution tothe donor.

A further variant of the system of FIG. 10 is shown in an alternatedotted line coupling to a second return needle 210 via a direct tubing212 connection from the outflow blood pump 204. The double needleenables return flow to be concurrent with inlet flow and a volumetricbuffer system such as an intermediate reservoir is not needed. Althoughless comfortable for the donor, two needle systems are more often usedthan single needle systems with therapeutic apheresis applications.

While there have been described above and illustrated in the drawingsvarious forms and modifications in accordance with the invention, itwill be appreciated that the invention is not limited thereto butencompasses all modifications and exemplifications falling within theterms of the appended claims.

What is claimed is:
 1. A system for separating filtrate from a fluidsuspension having at least one biological cellular component that ischaracterized by having a nonrigid cell membrane free of a rigid outercell wall, the cellular component being thereby subject to trauma whenstressed, the system comprising:a membrane separation device comprisingaseparation chamber, a cellular suspension input for conveying thecellular suspension into the chamber, a microporous filter membrane inthe chamber having pore openings sized to separate filtrate from thefluid suspension to leave within the chamber a concentrated suspensioncontaining the at least one cellular component that is subject totrauma, means rotating the membrane at a selected surface velocity tocreate movement of the fluid suspension within the chamber withoutsubstantial trauma to the cellular component for inducing transport ofthe cellular component from the membrane while the fluid suspension istransported to the membrane, means for withdrawing the filtrate from thechamber through the rotating membrane means, including a filtrate outputfor discharging the filtrate, and a cellular concentrate outlet fordischarging the cellular suspension from the chamber, and conduit meanscommunication with the membrane separation device and a source of thecellular suspension and includinginput conduit means associated with thecellular suspension input and including inlet pumping means fordelivering the cellular suspension from the source into the chamber,output conduit means associated with the cellular concentrate outlet andincluding outlet pumping means for discharging the cellular suspensionfrom the chamber without recirculation back into the chamber, andcontrol means interconnecting the input pumping means and the outputpumping means for maintaining a selected flow relationship between theinput and output pumping means to obtain a desired proportion in thefluid flow rate in the input conduit means in relation to the fluid flowrate in the output conduit means, thereby maintaining a desired optimalflow rate in the filtrate conduit means while the cellular suspensionproceeds in a single pass through the membrane separation device.
 2. Asystem according to claim 1wherein the input and output conduit meanscomprises flexible tubing, and where the input and output pumping meanscomprise separate roller pumps, one operatively contacting the inputconduit means and the other operatively contacting the output conduitmeans.
 3. A system according to claim 1 or 2wherein the output conduitmeans includes a reservoir for collecting a quantity of the cellularconcentrate and return pumping means responsive to the amount of fluidin the reservoir for returning the cellular concentrate collected in thereservoir to the source.
 4. A system according to claim 3wherein thereturn pumping means operates to convey fluid from the reservoir whenfluid amount in the reservoir equals or exceeds a predetermined leveland stops operation when the fluid amount is below the predeterminedlevel.
 5. A system according to claim 3wherein the return pumping meansis operatively connected with the input and output pumping means forceasing operation of the input and output pumping means during operationof the return pumping means.
 6. A system according to claim 1wherein thecellular suspension is whole blood, the filtrate is plasma, and thecellular concentrate includes red blood cells.
 7. A system according toclaim 1and further including additive conduit means communicating withthe outlet conduit means for introducing an additive solution to thecellular concentrate.
 8. A system according to claim 7and furtherincluding pumping means associated with the additive conduit means forpumping additive fluid to compensate for the volume of filtrateextracted by the membrane separation device.